Sequencing of Candidate Genes Selected by Beta Cell Experts in Monogenic Diabetes of Unknown Aetiology

Emma L Edghill; Jayne A L Minton; Christopher J Groves; Sarah E Flanagan; Ann-Marie Patch; Oscar Rubio-Cabezas; Maggie Shepherd; Sigurd Lenzen; Mark I McCarthy; Sian Ellard; Andrew T Hattersley

doi:10.6092/1590-8577/3864

Emma L Edghill Institute of Biomedical and Clinical Science, Peninsula Medical School. Exeter, United Kingdom
Jayne A L Minton Institute of Biomedical and Clinical Science, Peninsula Medical School. Exeter, United Kingdom
Christopher J Groves Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford. Oxford, United Kingdom
Sarah E Flanagan Institute of Biomedical and Clinical Science, Peninsula Medical School. Exeter, United Kingdom
Ann-Marie Patch Institute of Biomedical and Clinical Science, Peninsula Medical School. Exeter, United Kingdom
Oscar Rubio-Cabezas Institute of Biomedical and Clinical Science, Peninsula Medical School. Exeter, United Kingdom Department of Endocrinology, Hospital Infantil Universitario Niño Jesús; Department of Pediatrics, Universidad Autónoma de Madrid. Madrid Spain
Maggie Shepherd Institute of Health and Social Care, Peninsula Medical School. Exeter, United Kingdom
Sigurd Lenzen Institute of Clinical Biochemistry, Medizinische Hochschule. Hannover, Germany
Mark I McCarthy Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford. Oxford, United Kingdom
Sian Ellard Institute of Biomedical and Clinical Science, Peninsula Medical School. Exeter, United Kingdom
Andrew T Hattersley Institute of Biomedical and Clinical Science, Peninsula Medical School. Exeter, United Kingdom

DOI: https://doi.org/10.6092/1590-8577/3864

Keywords: Diabetes Mellitus, Type 2, Genetics, Insulin-Secreting Cells

Abstract

Context Approximately 39% of cases with permanent neonatal diabetes (PNDM) and about 11% with maturity onset diabetes of the young (MODY) have an unknown genetic aetiology. Many of the known genes causing MODY and PNDM were identified as being critical for beta cell function before their identification as a cause of monogenic diabetes. Objective We used nominations from the EU beta cell consortium EURODIA project partners to guide gene candidacy. Subjects Seventeen cases with permanent neonatal diabetes and 8 cases with maturity onset diabetes of the young. Main outcome measures The beta cell experts within the EURODIA consortium were asked to nominate 3 "gold", 3 "silver" and 4 "bronze" genes based on biological or genetic grounds. We sequenced twelve candidate genes from the list based on evidence for candidacy. Results Sequencing ISL1, LMX1A, MAFA, NGN3, NKX2.2, NKX6.1, PAX4, PAX6, SOX2, SREBF1, SYT9 and UCP2 did not identify any pathogenic mutations. Conclusion Further work is needed to identify novel causes of permanent neonatal diabetes and maturity onset diabetes of the young utilising genetic approaches as well as further candidate genes.

Image: Peninsula Medical School logo. Exeter, United Kingdom.

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References

Hattersley AT. Molecular genetics goes to the diabetes clinic. Clin Med 2005; 5:476-81. [PMID 16268330] (FULL TEXT: http://www.ingentaconnect.com/search/download;jsessionid=6k3b4hfgmifd3.alice?pub=infobike%3a%2f%2frcop%2fcm%2f2005%2f00000005%2f00000005%2fart00014&mimetype=application%2fpdf)

Murphy R, Ellard S, Hattersley AT. Clinical implications of a molecular genetic classification of monogenic beta-cell diabetes. Nat Clin Pract Endocrinol Metab 2008; 4:200-13. [PMID 18301398] (FULL TEXT: http://www.nature.com/nrendo/journal/v4/n4/full/ncpendmet0778.html)

McCarthy MI, Hattersley AT. Learning from molecular genetics: novel insights arising from the definition of genes for monogenic and type 2 diabetes. Diabetes 2008; 57:2889-98. [PMID 18971436] (FULL TEXT: http://diabetes.diabetesjournals.org/content/57/11/2889.long)

Froguel P, Vaxillaire M, Sun F, Velho G, Zouali H, Butel MO, et al. Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Nature 1992; 356:162-4. [PMID 1545870] (FULL TEXT: http://www.nature.com/nature/journal/v356/n6365/pdf/356162a0.pdf)

Hattersley AT, Turner RC, Permutt MA, Patel P, Tanizawa Y, Chiu KC, et al. Linkage of type 2 diabetes to the glucokinase gene. Lancet 1992; 339:1307-10. [PMID 1349989] (FULL TEXT: http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T1B-49K5BS8-3H2&_user=606145&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000031398&_version=1&_urlVersion=0&_userid=606145&md5=134b538160e3351c04972e0bad705ede)

Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, et al. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med 2004; 350:1838-49. [PMID 15115830] (FULL TEXT: http://content.nejm.org/cgi/content/full/350/18/1838)

Stoffers DA, Ferrer J, Clarke WL, Habener JF. Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. Nat Genet 1997; 17:138-9. [PMID 9326926] (FULL TEXT: http://www.nature.com/ng/journal/v17/n2/pdf/ng1097-138.pdf)

Sellick GS, Barker KT, Stolte-Dijkstra I, Fleischmann C, Coleman RJ, Garrett C, et al. Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nat Genet 2004; 36:1301-5. [PMID 15543146] (FULL TEXT: http://www.nature.com/ng/journal/v36/n12/full/ng1475.html)

Habener JF, Kemp DM, Thomas MK. Minireview: transcriptional regulation in pancreatic development. Endocrinology 2005; 146:1025-34. [PMID 15604203] (FULL TEXT: http://endo.endojournals.org/cgi/content/full/146/3/1025)

Perry JR, Frayling TM. New gene variants alter type 2 diabetes risk predominantly through reduced beta-cell function. Curr Opin Clin Nutr Metab Care 2008; 11:371-7. [PMID 18541994] (FULL TEXT: http://journals.lww.com/co-clinicalnutrition/pages/articleviewer.aspx?year=2008&issue=07000&article=00004&type=abstract)

Jensen J, Heller RS, Funder-Nielsen T, Pedersen EE, Lindsell C, Weinmaster G, et al Independent development of pancreatic alpha- and beta-cells from neurogenin3-expressing precursors: a role for the notch pathway in repression of premature differentiation. Diabetes 2000; 49:163-76. [PMID 10868931] (FULL TEXT: http://diabetes.diabetesjournals.org/content/49/2/163.long)

Sussel L, Kalamaras J, Hartigan-O'Connor DJ, Meneses JJ, Pedersen RA, Rubenstein JL, German MS. Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta cells. Development 1998; 125:2213-21. [PMID 9584121] (FULL TEXT: http://dev.biologists.org/cgi/reprint/125/12/2213)

Sosa-Pineda B, Chowdhury K, Torres M, Oliver G, Gruss P. The Pax4 gene is essential for differentiation of insulin-producing beta cells in the mammalian pancreas. Nature 1997; 386:399-402. [PMID 9121556] (FULL TEXT: http://www.nature.com/nature/journal/v386/n6623/pdf/386399a0.pdf)

St-Onge L, Sosa-Pineda B, Chowdhury K, Mansouri A, Gruss P. Pax6 is required for differentiation of glucagon-producing alpha-cells in mouse pancreas. Nature 1997; 387:406-9. [PMID 9163426] (FULL TEXT: http://www.nature.com/nature/journal/v387/n6631/full/387406a0.html)

Ahlgren U, Pfaff SL, Jessell TM, Edlund T, Edlund H. Independent requirement for ISL1 in formation of pancreatic mesenchyme and islet cells. Nature 1997; 385:257-60. [PMID 9000074] (FULL TEXT: http://www.nature.com/nature/journal/v385/n6613/pdf/385257a0.pdf)

Olbrot M, Rud J, Moss LG, Sharma A. Identification of beta-cell-specific insulin gene transcription factor RIPE3b1 as mammalian MafA. Proc Natl Acad Sci U S A 2002; 99:6737-42. [PMID 12011435] (FULL TEXT: http://www.pnas.org/content/99/10/6737.long)

Gradwohl G, Dierich A, LeMeur M, Guillemot F. neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. Proc Natl Acad Sci U S A 2000; 97:1607-11. [PMID 10677506] (FULL TEXT: http://www.pnas.org/content/97/4/1607.long)

Zhang C, Moriguchi T, Kajihara M, Esaki R, Harada A, Shimohata H, et al. MafA is a key regulator of glucose-stimulated insulin secretion. Mol Cell Biol 2005; 25:4969-76. [PMID 15923615] (FULL TEXT: http://mcb.asm.org/cgi/content/full/25/12/4969?view=long&pmid=15923615)

Nocerino V, Colombo C, Bonfanti R, Iafusco D, Barbetti F. Mutations in IAPP and NEUROG3 genes are not a common cause of permanent neonatal/infancy/childhood-onset diabetes. Diabet Med 2009; 26:660-1. [PMID 19538245] (FULL TEXT: http://www3.interscience.wiley.com/cgi-bin/fulltext/122304733/HTMLSTART)

Rubio-Cabezas O, Codner E, Jensen JN, Hodgson MI, Serup P, Ellard S, et al. Neurogenin 3 deficiency is a novel cause of per-manent neonatal diabetes and severe congenital diarrhea. Horm Res 2009; 72:61 (FULL TEXT: http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&ArtikelNr=239668&Ausgabe=250325&ProduktNr=224036&filename=239668.pdf)

Rudnick A, Ling TY, Odagiri H, Rutter WJ, German MS. Pancreatic beta cells express a diverse set of homeobox genes. Proc Natl Acad Sci U S A 1994; 91:12203-7. [PMID 7991607] (FULL TEXT: http://www.pnas.org/content/91/25/12203.full.pdf+html)

Zhao M, Amiel SA, Christie MR, Muiesan P, Srinivasan P, Littlejohn W, et al. Evidence for the presence of stem cell-like progenitor cells in human adult pancreas. J Endocrinol 2007; 195:407-14. [PMID 18000303] (FULL TEXT: http://joe.endocrinology-journals.org/cgi/content/full/195/3/407)

German MS, Wang J, Fernald AA, Espinosa R 3rd, Le Beau MM, Bell GI. Localization of the genes encoding two transcription factors, LMX1 and CDX3, regulating insulin gene expression to human chromosomes 1 and 13. Genomics 1994; 24:403-4. [PMID 7698771] (FULL TEXT: http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6WG1-45NJWJ2-15-1&_cdi=6809&_user=839424&_orig=search&_coverDate=11%2F15%2F1994&_sk=999759997&view=c&wchp=dGLzVtb-zSkWb&md5=2c1794fa5873e3f9cb721b2da6e75baf&ie=/sdarticle.pdf)

Iezzi M, Eliasson L, Fukuda M, Wollheim CB. Adenovirus-mediated silencing of synaptotagmin 9 inhibits Ca2+-dependent insulin secretion in islets. FEBS Lett 2005; 579:5241-6. [PMID 16165130] (FULL TEXT: http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T36-4H21H4H-1&_user=839424&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000045367&_version=1&_urlVersion=0&_userid=839424&md5=7a72bf23c285c7b50df8941c9792c1c9)

Foufelle F, Ferré P. New perspectives in the regulation of hepatic glycolytic and lipogenic genes by insulin and glucose: a role for the transcription factor sterol regulatory element binding protein-1c. Biochem J 2002; 366:377-91. [PMID 12061893] (FULL TEXT: http://www.biochemj.org/bj/366/0377/bj3660377.htm)

Shimajiri Y, Sanke T, Furuta H, Hanabusa T, Nakagawa T, Fujitani Y, et al. A missense mutation of Pax4 gene (R121W) is associated with type 2 diabetes in Japanese. Diabetes 2001; 50:2864-9. [PMID 11723072] (FULL TEXT: http://diabetes.diabetesjournals.org/content/50/12/2864.long)

Plengvidhya N, Kooptiwut S, Songtawee N, Doi A, Furuta H, Nishi M, et al. PAX4 mutations in Thais with maturity onset diabetes of the young. J Clin Endocrinol Metab 2007; 92:2821-6. [PMID 17426099] (FULL TEXT: http://jcem.endojournals.org/cgi/content/full/92/7/2821)

Eberle D, Clement K, Meyre D, Sahbatou M, Vaxillaire M, Le Gall A, et al. SREBF-1 gene polymorphisms are associated with obesity and type 2 diabetes in French obese and diabetic cohorts. Diabetes 2004; 53:2153-7. [PMID 15277400] (FULL TEXT: http://diabetes.diabetesjournals.org/content/53/8/2153.long)

Grarup N, Stender-Petersen KL, Andersson EA, Jørgensen T, Borch-Johnsen K, Sandbaek A, et al. Association of variants in the sterol regulatory element-binding factor 1 (SREBF1) gene with type 2 diabetes, glycemia, and insulin resistance: a study of 15,734 Danish subjects. Diabetes 2008; 57:1136-42. [PMID 18192539] (FULL TEXT: http://diabetes.diabetesjournals.org/content/57/4/1136.long)

Li J, Bergmann A, Reimann M, Schulze J, Bornstein SR, Schwarz PE. Genetic variation of Neurogenin 3 is slightly associated with hyperproinsulinaemia and progression toward type 2 diabetes. Exp Clin Endocrinol Diabetes 2008; 116:178-83. [PMID 18072012] (FULL TEXT: http://www.thieme-connect.com/ejournals/html/eced/doi/10.1055/s-2007-992156)